Poria cocos polysaccharide-loaded Alum Pickering emulsion as vaccine adjuvant to enhance immune responses.

Traditional Alum adjuvants mainly elicit a Th2 humoral immune response, but fail to generate a robust Th1 cellular immune response. However, the cellular immune response is essential for vaccination against cancer and a number of chronic infectious diseases, including human immunodeficiency virus infection and tuberculosis. In our previous study, we demonstrated that the polysaccharide from Poria cocos (PCP) has the potential to serve as an immunologic stimulant, enhancing both humoral and cellular immune responses. However, this effect was only observed at high concentrations. In this study, to enhance the immune-stimulation effect of PCP and modify the type of immune response elicited by Alum adjuvant, we successfully developed a Pickering emulsion delivery system (PCP-Al-Pickering) using PCP-loaded Alhydrogel particles as the stabilizer. After optimization, the Pickering emulsion exhibited excellent storage capacity and effectively adsorbed the PCP and antigen. As an adjuvant delivery system, the PCP-Al-Pickering emulsion facilitated the antigen uptake by macrophages, increased the recruitment of cells at injection sites, improved the activation of dendritic cells in draining lymph nodes, elicited a potent and durable antibody response, and promoted the activation of CD4+ and CD8+ T cells. Importantly, the PCP-Al-Pickering emulsion adjuvant elicited a balanced Th1 and Th2 immune response, in comparison to Alum adjuvant. The PCP-Al-Pickering emulsion may serve as a safe and promising adjuvant delivery system to enhance immune responses.

Current and future directions in network biology.

Summary: Network biology is an interdisciplinary field bridging computational and biological sciences that has proved pivotal in advancing the understanding of cellular functions and diseases across biological systems and scales. Although the field has been around for two decades, it remains nascent. It has witnessed rapid evolution, accompanied by emerging challenges. These stem from various factors, notably the growing complexity and volume of data together with the increased diversity of data types describing different tiers of biological organization. We discuss prevailing research directions in network biology, focusing on molecular/cellular networks but also on other biological network types such as biomedical knowledge graphs, patient similarity networks, brain networks, and social/contact networks relevant to disease spread. In more detail, we highlight areas of inference and comparison of biological networks, multimodal data integration and heterogeneous networks, higher-order network analysis, machine learning on networks, and network-based personalized medicine. Following the overview of recent breakthroughs across these five areas, we offer a perspective on future directions of network biology. Additionally, we discuss scientific communities, educational initiatives, and the importance of fostering diversity within the field. This article establishes a roadmap for an immediate and long-term vision for network biology. Availability and implementation: Not applicable.

The Structural Characterization of a Polysaccharide from the Dried Root of Salvia miltiorrhiza and Its Use as a Vaccine Adjuvant to Induce Humoral and Cellular Immune Responses.

In order to supplement the research gap concerning Salvia miltiorrhiza polysaccharide extracted from Danshen in NMR analysis, and to clarify its immune enhancement effect as an adjuvant, we isolated and purified SMPD-2, which is composed of nine monosaccharides such as Ara, Gal, and Glc from Danshen. Its weight average molecular weight was 37.30 ± 0.096 KDa. The main chain was mainly composed of →4)-α-D-Galp-(1→, →3,6)-ß-D-Glcp-(1→ and a small amount of α-L-Araf-(1→. After the subcutaneous injection of SMPD-2 as an adjuvant to OVA in mice, we found that it enhanced the immune response by activating DCs from lymph nodes, increasing OVA-specific antibody secretion, stimulating spleen lymphocyte activation, and showing good biosafety. In conclusion, SMPD-2 could be a promising candidate for an adjuvant.

Exposure of benzo[a]pyrene induces HCC exosome-circular RNA to activate lung fibroblasts and trigger organotropic metastasis.

BACKGROUND: Benzo[a]pyrene (B[a]P), a carcinogen pollutant produced by combustion processes, is present in the western diet with grilled meats. Chronic exposure of B[a]P in hepatocellular carcinoma (HCC) cells promotes metastasis rather than primary proliferation, implying an unknown mechanism of B[a]P-induced malignancy. Given that exosomes carry bioactive molecules to distant sites, we investigated whether and how exosomes mediate cancer-stroma communications for a toxicologically associated microenvironment. METHOD: Exosomes were isolated from B[a]P stimulated BEL7404 HCC cells (7404-100Bap Exo) at an environmental relevant dose (100 nmol/L). Lung pre-education animal model was prepared via injection of exosomes and cytokines. The inflammatory genes of educated lungs were evaluated using quantitative reverse transcription PCR array. HCC LM3 cells transfected with firefly luciferase were next injected to monitor tumor burdens and organotropic metastasis. Profile of B[a]P-exposed exosomes were determined by ceRNA microarray. Interactions between circular RNA (circRNA) and microRNAs (miRNAs) were detected using RNA pull-down in target lung fibroblasts. Fluorescence in situ hybridization and RNA immunoprecipitation assay was used to evaluate the "on-off" interaction of circRNA-miRNA pairs. We further developed an adeno-associated virus inhalation model to examine mRNA expression specific in lung, thereby exploring the mRNA targets of B[a]P induced circRNA-miRNA cascade. RESULTS: Lung fibroblasts exert activation phenotypes, including focal adhesion and motility were altered by 7404-100Bap Exo. In the exosome-educated in vivo model, fibrosis factors and pro-inflammatory molecules of are up-regulated when injected with exosomes. Compared to non-exposed 7404 cells, circ_0011496 was up-regulated following B[a]P treatment and was mainly packaged into 7404-100Bap Exo. Exosomal circ_0011496 were delivered and competitively bound to miR-486-5p in recipient fibroblasts. The down-regulation of miR-486-5p converted fibroblast to cancer-associated fibroblast via regulating the downstream of Twinfilin-1 (TWF1) and matrix metalloproteinase-9 (MMP9) cascade. Additionally, increased TWF1, specifically in exosomal circ_0011496 educated lungs, could promote cancer-stroma crosstalk via activating vascular endothelial growth factor (VEGF). These modulated fibroblasts promoted endothelial cells angiogenesis and recruited primary HCC cells invasion, as a consequence of a pre-metastatic niche formation. CONCLUSION: We demonstrated that B[a]P-induced tumor exosomes can deliver circ_0011496 to activate miR-486-5p/TWF1/MMP9 cascade in the lung fibroblasts, generating a feedback loop that promoted HCC metastasis.

Structural characterization and adjuvant activity of a water soluble polysaccharide from Poria cocos.

Adjuvants, as the essential component of vaccines, are crucial in enhancing the magnitude, breadth and durability of immune responses. Unfortunately, commonly used Alum adjuvants predominantly provoke humoral immune response, but fail to evoke cellular immune response, which is crucial for the prevention of various chronic infectious diseases and cancers. Thus, it is necessary to develop effective adjuvants to simultaneously induce humoral and cellular immune response. In this work, we obtained a water soluble polysaccharide isolated and purified from Poria cocos, named as PCP, and explored the possibility of PCP as a vaccine adjuvant. The PCP, with Mw of 20.112 kDa, primarily consisted of →6)-α-D-Galp-(1→, with a small amount of →3)-ß-D-Glcp-(1 â†’ and →4)-ß-D-Glcp-(1→. Our results demonstrated that the PCP promoted the activation of dendritic cells (DCs) and macrophages in vitro. As the adjuvant to ovalbumin, the PCP facilitated the activation of DCs in lymph nodes, and evoked strong antibody response with a combination of Th1 and Th2 immune responses. Moreover, compared to Alum adjuvant, the PCP markedly induced a potent cellular response, especially the cytotoxic T lymphocytes response. Therefore, we confirmed that the PCP has great potential to be an available adjuvant for simultaneously inducing humoral and cellular immune responses.

Research and application progress of microbial ß-mannanases: a mini-review.

Mannan is a predominant constituent of cork hemicellulose and is widely distributed in various plant tissues. ß-Mannanase is the principal mannan-degrading enzyme, which breaks down the ß-1,4-linked mannosidic bonds in mannans in an endo-acting manner. Microorganisms are a valuable source of ß-mannanase, which exhibits catalytic activity in a wide range of pH and temperature, making it highly versatile and applicable in pharmaceuticals, feed, paper pulping, biorefinery, and other industries. Here, the origin, classification, enzymatic properties, molecular modification, immobilization, and practical applications of microbial ß-mannanases are reviewed, the future research directions for microbial ß-mannanases are also outlined.

Changes of biochemical factors and the effect on recurrence of medullary thyroid carcinoma after surgery.

Objective: Medullary thyroid carcinoma (MTC) is a rare malignancy secreting calcitonin (Ctn). We aimed to analyze the relationship between Ctn levels at different time points in patients with MTC, and evaluate its predictive effect on recurrence. Methods: A retrospective study of patients diagnosed with MTC in a large medical center were conducted in northern China. The interrelationships between preoperative Ctn, normalization of postoperative serum Ctn at the first month (NPS), and long-term biochemical cure as well as their predicting roles on structural recurrence were assessed. Results: A total of 212 patients were included in this study. The median follow-up time was 59.5 months. The 5- and 10-year cumulative disease-free survival rates were 81.5 % and 66.8 %, respectively. NPS (OR: 216.33, 95 % CI: 28.69-1631.09, P < 0.001) and absence of structural recurrence (OR: 61.71, 95 % CI: 3.90-975.31; P = 0.003) were associated with biochemical cure. Non-biochemical cure (OR: 28.76; 95 % CI: 2.84-290.86; P = 0.004, HR: 14.63, 95 % CI: 2.27-94.07, P = 0.005), larger tumor size (OR: 8.79, 95 % CI: 2.12-36.40, P = 0.003, HR: 5.41, 95 % CI: 2.04-14.37, P = 0.001), and multifocality (OR: 4.02, 95 % CI: 1.06-15.17, P = 0.040, HR: 3.00, 95 % CI: 1.18-7.60, P = 0.021) were unfavorable independent predictors of structural recurrence and disease-free survival. For sporadic MTC confined to the thyroid lobe, there was no difference in biochemical or structural prognosis between the different surgeries in the subgroup analysis. Conclusions: NPS, rather than preoperative Ctn, predicted long-term biochemical cure for MTC. Non-biochemical cure, larger tumor burden including larger tumor size and multifocality at initial surgery, served as worse prognostic predictors.

Preparation and characterization of pickering emulsion stabilized by lovastatin nanoparticles for vaccine adjuvants.

While research on mevalonate inhibitors as vaccine adjuvants has made great progress to enhance the effectiveness of the vaccine, co delivery of lovastatin and antigens (OVA) remains an enormous challenge. Here, we encapsulated lovastatin into PLGA nanoparticles. PLGA loading lovastatin was further emulsified with squalene to prepare Pickering emulsion. The emulsification conditions of Pickering emulsion were optimized, and the optimal preparation conditions were obtained. After loading lovastatin and OVA, the size and zeta potential of LS-PPAS/OVA was 1043.33 nm and -22.07 mv, the adsorption rate of OVA was 63.34 %. The adsorbing of LS-PLGA nanoparticles on the surface of squalene in Pickering emulsions was demonstrated by Fluorescent confocal microscopy. After immunization, LS-PPAS enhanced the activation of dendritic cells in lymph nodes, further study found LS-PPAS not only elicited elevated levels of OVA-specific IgG and its subtypes, but also promoted the secretion of TNF-α, IFN-γ, and IL-6 in serum as a marker of cellular immunity. Importantly, LS-PPAS showed sufficient security through monitoring levels of biochemical parameters in serum and pathological observation of organ following vaccinations. LS-PPAS may act as a promising vaccine carrier to produce strong humoral and cellular immunity with acceptable safety.

Cistanche deserticola polysaccharide-functionalized dendritic fibrous nano-silica as oral vaccine adjuvant delivery enhancing both the mucosal and systemic immunity.

Oral vaccines are a safe and convenient alternative to injected vaccines and have great potential to prevent major infectious diseases. However, the harsh gastrointestinal (GI) environment, mucus barriers, low immunogenicity, and lack of effective and safe mucosal adjuvants are the major challenges for oral vaccine delivery. In recent years, nanoparticle-based strategies have become attractive for improving oral vaccine delivery. Here, the dendritic fibrous nano-silica (DFNS) grafted with Cistanche deserticola polysaccharide (CDP) nanoparticles (CDP-DFNS) were prepared and investigated how to impact the immune responses. CDP-DFNS facilitated the antigen uptake in mouse bone marrow-derived dendritic cells (BMDCs), and induce the activation of DCs in vitro. Furthermore, in vivo experiments, the result showed that the uptake efficiency by Peyer's patches (PPs) of CDP-DFNS/BSA was the best. And CDP-DFNS/BSA then significantly activated the DCs in lamina propria (LP), and T/B cells in PPs and mesenteric lymph nodes (MLNs). Moreover, the memory T cell responses in later period of vaccination was stronger than other groups. In addition, CDP-DFNS/BSA enhanced BSA-specific antibody IgG, IgA production, and SIgA secretion, was effective at inducing a strong mixed Th1/Th2 response and mucosal antibody responses. These results indicated that CDP-DFNS deserves further consideration as an oral vaccine adjuvant delivery system.

Application of Acetate as a Substrate for the Production of Value-Added Chemicals in Escherichia coli.

At present, the production of the majority of valuable chemicals is dependent on the microbial fermentation of carbohydrate substrates. However, direct competition is a potential problem for microbial feedstocks that are also used within the food/feed industries. The use of alternative carbon sources, such as acetate, has therefore become a research focus. As a common organic acid, acetate can be generated from lignocellulosic biomass and C1 gases, as well as being a major byproduct in microbial fermentation, especially in the presence of an excess carbon source. As a model microorganism, Escherichia coli has been widely applied in the production of valuable chemicals using different carbon sources. Recently, several valuable chemicals (e.g., succinic acid, itaconic acid, isobutanol, and mevalonic acid) have been investigated for synthesis in E. coli using acetate as the sole carbon source. In this review, we summarize the acetate metabolic pathway in E. coli and recent research into the microbial production of chemical compounds in E. coli using acetate as the carbon source. Although microbial synthetic pathways for different compounds have been developed in E. coli, the production titer and yield are insufficient for commercial applications. Finally, we discuss the development prospects and challenges of using acetate for microbial fermentation.

Structural Characterization and In Vitro Anti-Inflammatory Activity of Polysaccharides Isolated from the Fruits of Rosa laevigata.

RLPa-2 (Mw 15.6 kDa) is a polysaccharide isolated from Rosa laevigata Michx. It consists of arabinose (Ara), galactose (Gal), rhamnose (Rha), glucose (Glc), xylose (Xyl), and galacturonic acid (Gal-UA) with a molar ratio of 1.00:0.91:0.39:0.34:0.25:0.20. Structural characterization was performed by methylation and NMR analysis, which indicated that RLPa-2 might comprise →6)-α-D-Galp-(1→, →4)-α-D-GalpA-(1→, α-L-Araf-(1→, →2,4)-α-D-Glcp-(1→, ß-D-Xylp, and α-L-Rhap. In addition, the bioactivity of RLPa-2 was assessed through an in vitro macrophage polarization assay. Compared to positive controls, there was a significant decrease in the expression of M1 macrophage markers (CD80, CD86) and p-STAT3/STAT3 protein. Additionally, there was a down-regulation in the production of pro-inflammatory mediators (NO, IL-6, TNF-α), indicating that M1 macrophage polarization induced with lipopolysaccharide (LPS) and interferon-γ (IFN-γ) stimulation could be inhibited by RLPa-2. These findings demonstrate that the RLPa-2 might be considered as a potential anti-inflammatory drug to reduce inflammation.

An Inducible CRISPR-dCas9-Based Transcriptional Repression System for Cancer Therapy.

Gene therapy has been adapted for improving malignant tumor treatment. However, pharmacotherapies targeting cancer remain limited and are generally inapplicable for rare disease patients. Oleanolic acid (OA) is a plant-derived triterpenoid that is frequently used in Chinese medicine as a safe but slow-acting treatment for many disorders. Here, the congruent pharmacological activities of OA and CRISPR-dCas9 in targeting AURKA or KDM1A and improving disease-specific prognosis and used a synthetic-biology-inspired design principle to engineer a therapeutic gene circuit that enables a concerted action of both drugs are utilized. In particular, the OA-triggered CRISPR-dCas9 transcriptional repression system rapidly and simultaneously attenuated lung and thyroid cancer. Collectively, this work shows that rationally engineered synthetic gene circuits are capable of treating multifactorial diseases in a synergistic manner by multiplexing the targeting efficiencies of single therapeutics.

Analysis of Surgical Outcomes in Endoscopic-Assisted Lateral Neck Dissection.

BACKGROUND: Currently, endoscopic-assisted lateral neck dissection (EALND) is performed to reduce postoperative scarring of the anterior neck. This study aimed to compare surgical outcomes between EALND and conventional open lateral neck dissection (COLND) for papillary thyroid carcinoma (PTC) with lateral lymph node metastases (LNM). METHODS: The study reviewed 103 PTC patients who were classified on the basis of surgical type and statistically compared using propensity score matching analysis. RESULTS: The mean operation time is longer, and the cost of surgery is higher in the EALND group than COLND group (all p < 0.05). The numbers of retrieved and positive level II LNs, the rate of level II LNs detection between two groups do not differ significantly (all p > 0.05). The incidence of postoperative neck numbness is lower, and patients are more satisfied with postoperative neck scarring in the EALND group than COLND group (all p < 0.05). The common complications of two groups are transient recurrent laryngeal nerve injury and transient hypoparathyroidism. CONCLUSIONS: EALND is safe and feasible compared with COLND. The incision is more aesthetically satisfactory, which makes EALND a surgical approach for PTC patients with lateral LNM. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:2221-2227, 2024.

TestFit: A plug-and-play one-pass test time method for medical image segmentation.

Deep learning (DL) based methods have been extensively studied for medical image segmentation, mostly emphasizing the design and training of DL networks. Only few attempts were made on developing methods for applying DL models in test time. In this paper, we study whether a given off-the-shelf segmentation network can be stably improved on-the-fly during test time in an online processing-and-learning fashion. We propose a new online test-time method, called TestFit, to improve results of a given off-the-shelf DL segmentation model in test time by actively fitting the test data distribution. TestFit first creates a supplementary network (SuppNet) from the given trained off-the-shelf segmentation network (this original network is referred to as OGNet) and applies SuppNet together with OGNet for test time inference. OGNet keeps its hypothesis derived from the original training set to prevent the model from collapsing, while SuppNet seeks to fit the test data distribution. Segmentation results and supervision signals (for updating SuppNet) are generated by combining the outputs of OGNet and SuppNet on the fly. TestFit needs only one pass on each test sample - the same as the traditional test model pipeline - and requires no training time preparation. Since it is challenging to look at only one test sample and no manual annotation for model update each time, we develop a series of technical treatments for improving the stability and effectiveness of our proposed online test-time training method. TestFit works in a plug-and-play fashion, requires minimal hyper-parameter tuning, and is easy to use in practice. Experiments on a large collection of 2D and 3D datasets demonstrate the capability of our TestFit method.

Engineering Escherichia coli for Isobutanol Production from Xylose or Glucose-Xylose Mixture.

Aiming to overcome the depletion of fossil fuels and serious environmental pollution, biofuels such as isobutanol have garnered increased attention. Among different synthesis methods, the microbial fermentation of isobutanol from raw substrate is a promising strategy due to its low cost and environmentally friendly and optically pure products. As an important component of lignocellulosics and the second most common sugar in nature, xylose has become a promising renewable resource for microbial production. However, bottlenecks in xylose utilization limit its wide application as substrates. In this work, an isobutanol synthetic pathway from xylose was first constructed in E. coli MG1655 through the combination of the Ehrlich and Dahms pathways. The engineering of xylose transport and electron transport chain complexes further improved xylose assimilation and isobutanol production. By optimizing xylose supplement concentration, the recombinant E. coli strain BWL4 could produce 485.35 mg/L isobutanol from 20 g/L of xylose. To our knowledge, this is the first report related to isobutanol production using xylose as a sole carbon source in E. coli. Additionally, a glucose-xylose mixture was utilized as the carbon source. The Entner-Doudorof pathway was used to assimilate glucose, and the Ehrlich pathway was applied for isobutanol production. After carefully engineering the recombinant E. coli, strain BWL9 could produce 528.72 mg/L isobutanol from a mixture of 20 g/L glucose and 10 g/L xylose. The engineering strategies applied in this work provide a useful reference for the microbial production of isobutanol from xylose or glucose-xylose mixture.

Synthesis of isobutanol using acetate as sole carbon source in Escherichia coli.

BACKGROUND: With concerns about depletion of fossil fuel and environmental pollution, synthesis of biofuels such as isobutanol from low-cost substrate by microbial cell factories has attracted more and more attention. As one of the most promising carbon sources instead of food resources, acetate can be utilized by versatile microbes and converted into numerous valuable chemicals. RESULTS: An isobutanol synthetic pathway using acetate as sole carbon source was constructed in E. coli. Pyruvate was designed to be generated via acetyl-CoA by pyruvate-ferredoxin oxidoreductase YdbK or anaplerotic pathway. Overexpression of transhydrogenase and NAD kinase increased the isobutanol titer of recombinant E. coli from 121.21 mg/L to 131.5 mg/L under batch cultivation. Further optimization of acetate supplement concentration achieved 157.05 mg/L isobutanol accumulation in WY002, representing the highest isobutanol titer by using acetate as sole carbon source. CONCLUSIONS: The utilization of acetate as carbon source for microbial production of valuable chemicals such as isobutanol could reduce the consumption of food-based substrates and save production cost. Engineering strategies applied in this study will provide a useful reference for microbial production of pyruvate derived chemical compounds from acetate.

Alanine dehydrogenases from four different microorganisms: characterization and their application in L-alanine production.

BACKGROUND: Alanine dehydrogenase (AlaDH) belongs to oxidoreductases, and it exists in several different bacteria species and plays a key role in microbial carbon and nitrogen metabolism, spore formation and photosynthesis. In addition, AlaDH can also be applied in biosynthesis of L-alanine from cheap carbon source, such as glucose. RESULTS: To achieve a better performance of L-alanine accumulation, system evaluation and comparison of different AlaDH with potential application value are essential. In this study, enzymatic properties of AlaDH from Bacillus subtilis 168 (BsAlaDH), Bacillus cereus (BcAlaDH), Mycobacterium smegmatis MC2 155 (MsAlaDH) and Geobacillus stearothermophilus (GsAlaDH) were firstly carefully investigated. Four different AlaDHs have few similarities in optimum temperature and optimum pH, while they also exhibited significant differences in enzyme activity, substrate affinity and enzymatic reaction rate. The wild E. coli BL21 with these four AlaDHs could produce 7.19 g/L, 7.81 g/L, 6.39 g/L and 6.52 g/L of L-alanine from 20 g/L glucose, respectively. To further increase the L-alanine titer, competitive pathways for L-alanine synthesis were completely blocked in E. coli. The final strain M-6 could produce 80.46 g/L of L-alanine with a yield of 1.02 g/g glucose after 63 h fed-batch fermentation, representing the highest yield for microbial L-alanine production. CONCLUSIONS: Enzyme assay, biochemical characterization and structure analysis of BsAlaDH, BcAlaDH, MsAlaDH and GsAlaDH were carried out. In addition, application potential of these four AlaDHs in L-alanine productions were explored. The strategies here can be applied for developing L-alanine producing strains with high titers.

Response surface optimization of poly-ß-hydroxybutyrate synthesized by Bacillus cereus L17 using acetic acid as carbon source.

A strain of Bacillus that can tolerate 10 g/L acetic acid and use the volatile fatty acids produced by the hydrolysis and acidification of activated sludge to produce polyhydroxyalkanoate was screened from the activated sludge of propylene oxide saponification wastewater. The strain was identified by 16S rRNA sequencing and phylogenetic tree analysis and was named Bacillus cereus L17. Various characterization methods showed that the polymer synthesized by strain L17 is poly-ß-hydroxybutyrate, which has low crystallinity, good ductility and toughness, high thermal stability and a low polydispersity coefficient. It has wide thermoplastic material operating space as well as industrial and medicinal applications. The optimal fermentation conditions were determined by single factor optimization. Then, Plackett-Burman and Box-Behnken design experiments were carried out according to the single factor optimization results, and the response surface optimization was completed. The final results were: initial pH 6.7, temperature 25 °C, and loading volume 124 mL. The verification experiment showed that the yield of poly-ß-hydroxybutyrate after optimization increased by 35.2 % compared to that before optimization.

Cadmium promotes colorectal cancer metastasis through EGFR/Akt/mTOR signaling cascade and dynamics.

Cadmium (Cd) is a hazardous environmental heavy metal with a prolonged biological half-life. Due to the main route of foodborne exposure, the intestinal tract is particularly vulnerable to Cd-induced toxicity. However, the chronic toxicity and underlying mechanisms of Cd in intestinal diseases, including colorectal cancer (CRC), still remain vague. Herein, we aim to investigate the long-term effects of Cd exposure on CRC development and the key signaling event. Our findings indicate that chronic and low-dose exposure to Cd promoted the invasion and metastasis capability of CRC cells in vitro and in mice, with a marginal increase in cell growth. The expression of cell junction-related genes was down-regulated while those molecules that facilitate cell mobility were significantly increased by Cd exposure. Epidermal growth factor receptor (EGFR) signaling was identified to play the dominant role in Cd-promoted CRC metastasis. Interestingly, Cd activated EGFR in a non-canonical manner that exhibited distinct signaling dynamics from the canonical ligand. In contrast to EGF, which induced transient EGFR signaling and ERK activation, Cd promoted sustained EGFR signaling to trigger Akt/mTOR cascade. The unique signaling dynamics of EGFR induced by Cd provoked responses that preferably enhanced the metastatic capacity rather than the growth. Furthermore, blockade of EGFR abrogated the promoting effects of Cd on the liver metastasis of CRC cells. In conclusion, this study provides a better understanding of the long-term influences of environmental Cd on CRC metastasis and reveals the unique EGFR signaling dynamics induced by Cd exposure.